ODAC Unanimously Votes to Recommend Randomized Data for Approval of PI3K Inhibitors in Hematologic Cancers

In a 16 to 0 vote, with 1 abstention, the FDA’s Oncologic Drugs Advisory Committee voted in support of basing future approvals for PI3K inhibitors on randomized data instead of single-arm clinical trials.

In a 16 to 0 vote, with 1 abstention, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in support of basing future approvals for PI3K inhibitors on randomized data instead of single-arm clinical trials.1,2

Currently, 4 PI3K inhibitors are approved by the FDA in hematologic malignancies based on single-arm data: idelalisib (Zydelig), copanlisib (Aliqopa), duvelisib (Copiktra), and umbralisib (Ukoniq), the latter of which was recently withdrawn from market.3 All 4 drugs have shown durable overall response rates or improvements in progression-free survival (PFS). However, 6 post-marketing randomized controlled trials have shown a potential detriment in overall survival (OS) and serious and potentially deadly adverse effects.

“I voted yes,” Christopher Lieu, MD, associate director for Clinical Research and co-director of Gastrointestinal Medical Oncology at the University of Colorado Cancer Center, said. “When you look at the significant concern that OS end points for indolent cancers can be costly and extremely time consuming, the utilization of PFS benefit as an end point for regulatory approval is potentially more reasonable for therapies with limited toxicity. It’s likely not reasonable in a situation where therapies have significant toxicities, and agents with significant toxicity may lead to confounders to PFS,” Lieu added.

“Sponsors have an obligation to demonstrate their products are safe and effective. The observed OS estimates, especially considering prior information, observed toxicity profiles, and questionable dose selection do not adequately rule out harm or support a conclusion that these products are safe,” the FDA said during the hearing.

During the hearing, the committee reviewed the current indications for each agent. Idelalisib is approved in combination with rituximab (Rituximab) for patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. However, the panel noted that Gilead, the drug developer, has since withdrawn the drug from the market for relapsed follicular lymphoma and small lymphocytic lymphoma (SLL) after failing to show confirmation of clinical benefit and safety. Also of concern to the panel is the accompanying boxed warning for fatal and serious toxicities, including hepatic toxicities, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.

Copanlisib is approved for patients with relapsed follicular lymphoma who have received at least 2 prior systemic therapies. The drug also comes with a warning that approximately 1 in 5 patients who received the drug alone were at risk of serious, including fatal, infections, the most common of which was pneumonia.

Duvelisib is approved for patients with relapsed/refractory CLL or SLL who have received at least 2 prior therapies. Similarly, the drug comes with a safety warning that 31% of patients who received the drug had fatal and/or serious infections. Of note, the agent’s indication for use in patients with relapsed/refractory follicular lymphoma following at least 2 prior systemic therapies was voluntarily withdrawn.

Umbralisib is indicated for patients with relapsed/refractory marginal zone lymphoma (MZL) who have received at least 1 prior CD20-directed therapy and relapsed/refractory follicular lymphoma who have received at least 3 prior lines of systemic therapy. On February 3, 2022, the FDA issued a warning that it was “investigating a possible increased risk of death with umbralisib. The FDA determined that initial findings from a clinical trial evaluating duvelisib to treat a related type of cancer found a possible increased risk of death in patients taking the medicine.”

“I voted yes,” Massimo Cristofanilli, MD, director of Breast Medical Oncology, associate director of Precision Oncology, Meyer Cancer Center (MCC), and co-leader of the MCC Breast Cancer Disease Management Team, Weill Cornell Medicine and NewYork-Presbyterian,said. “It’s very clear from these studies that there is a class effect of toxicity that we need to keep in mind for the future with regard to dose-finding studies, and randomized studies are the only way to address acute and chronic toxicity to see whether these drugs have a future in hematologic malignancies,” he added.

Notably, on April 15, 2022, TG Therapeutics, the drug developer of umbralisib, announced they were voluntarily withdrawing the pending biologics license application and supplemental new drug application for the combination of ublituximab and umbralisib for patients with CLL and SLL. The decision was based on updated OS data from the phase 3 UNITY-CLL trial (NCT02612311) that failed to show an improvement in OS with the combination. The company also announced withdrawal of its MZL and follicular lymphoma indications.

“With the available data, you at least hope to see a trend toward OS. The bottom line is: if we aren’t improving length of life with any therapy but exposing patients to toxicity and therefore decreasing their quality of life: Are we truly helping our patients? I don’t believe so,” Lieu concluded.


  1. Meeting of the oncologic drugs advisory committee (ODAC) day 1. FDA. Accessed April 21, 2022. https://www.youtube.com/watch?v=x6Wckege64o
  2. PI3K inhibitors in hematologic malignancies ODAC briefing document. FDA. Accessed April 21, 2022. https://www.fda.gov/media/157762/download
  3. FDA’s cancer advisory committee to evaluate safety of PI3K inhibitors. News release. BioSpace. April 20, 2022. Accessed April 21, 2022. https://bit.ly/3L7l4jA
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